Hyaline articular cartilage is well known as a specialized avascular tissue composed of chondrocytes embedded in a matrix consisting mainly of Collagen Type II and glycosaminoglycans, such as hyaluronic acid and chondroitin sulphate. Its main function is to allow smooth articulation of weight-bearing joints and to cushion the underlying bone from transmitted compressive and tensile forces involved in joint movement. Hyaline cartilage has an extremely low coefficient of friction for surface to surface contact.
Due to the considerable forces acting, for example on the knee joint, articular cartilage at the knee joint is especially prone to damage from acute trauma as well as from long-term degenerative disease. Owing to its avascular nature, articular cartilage has very limited capacity for repair and partial thickness defects do not heal spontaneously. Full thickness injuries that penetrate the subchondral bone, however, can undergo repair through mobilization of marrow-derived stem cells (MSC) from bone marrow into the blood clot at the site of injury.
Microfracture surgery is well known and takes advantage of this repair mechanism by creating tiny fractures in the subchondral bone through an arthroscopic technique. Subchondral drilling is a variant of microfracture surgery in which a drill, burr or Kirschner wire is used to create drill holes into subchondral bone rather than awls. These procedures are best used in young patients with 80% of those treated showing long term functional improvement. It is believed that microfracture surgery is less useful for lesions more than 15 mm in size, and in older and overweight patients.
The defect is eventually replaced by a hybrid of fibrocartilage and hyaline-like cartilage rather than the original hyaline cartilage. This change can be clearly demonstrated on T2-weighted MRI scans of the knee. The replacement tissue is inferior from a biomechanical standpoint as it is composed mainly of Collagen Type I and seems to be better at resisting tensile forces rather than compressive forces as found in the knee joint. Furthermore, while fibrocartilage does reduce friction when compared to bare bone, it does so to a lesser degree than hyaline cartilage alone. While many patients have shown functional improvement in the first year after surgery, there may be subsequent long term deterioration especially in athletes.
There is significant interest in modifying the basic microfracture technique to see if it is possible to induce formation of replacement hyaline cartilage rather than fibrocartilage. Autologous MSCs cultured in-vitro have been shown to repair full thickness defects, with formation of hyaline cartilage and reconstitution of underlying subchondral bone. Furthermore, the replacement tissue was demonstrated to have superior mechanical properties to normal repair tissue.
The drawbacks of using autologous MSCs are the need for painful bone marrow harvesting and subsequent cell culture which requires specialized facilities. In contrast, autologous peripheral blood-derived stem cells (PSC) are harvested from peripheral blood after stimulation with G-CSF (granulocyte colony stimulating factor) using a technique similar to plasmapheresis. A significant quantity (approximately 100 ml) can be collected in a single session, which can be frozen for future use at a later date for multiple procedures without the need for cell culture.
However, PSCs have limited potential to differentiate into cartilage compared with bone marrow harvested cells. When compared with MSCs, they lack telomerase activity and display significant telomere shortening. In cell culture, PSCs reach their Hayflick limit (i.e. the number of times a cell will divide before it stops due to the telomere reaching a critical length) about 20-25 days after isolation and become senescent. The limited expansion potential of PSCs has safety benefits in that all repair activity should have ceased within a month of the final injection, and should not give long term unexpected side effects like ectopic implantation. Furthermore, the lack of telomerase significantly limits the tumourigenic potential of these cells, which is a latent risk in stem cell therapy.
Other techniques to improve cartilage regeneration have included the use of polymer scaffolds, growth factors, hyaluronic acid, and autologous chondrocyte transplantation, either alone or in combination. Despite the previous studies and methods, improvements to the process of neochondrogenesis can be made.